The kinase's action mechanism is to transfer phosphate groups from high-energy donor molecules (e.g., ATP) to specific molecules, which is a process called phosphorylation. Protein kinases alter the activities of specific proteins through phosphorylation so as to control and regulate protein-associated signal transduction and other effects on cells. Due to the importance of protein kinases in cell signaling, the selectivity of some small molecule compounds for specific kinases will be helpful for further understanding on the cell signaling process. Meanwhile, small molecule compounds control the functions of cells by modulating the activities of kinases, which makes protein kinases become good drug targets in the treatment of clinical diseases.
Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, plays a key role in signal transduction in hematopoietic cells (except T lymphocytes and plasma cells), especially in the B cells which play an important role in the pathogenesis of autoimmune and inflammatory diseases. Btk has shown good clinical efficacy in many serious refractory diseases, such as rheumatoid arthritis, lymphoma and leukemia.
Btk plays a critical role in the process of B-cell development, differentiation, proliferation, activation and survival. The effect of Btk on B cells is achieved by controlling B-cell receptor (BCR) signaling pathway. Btk locates at adjacent downstream of the BCR. Btk passes down the signal upon BCR stimulation, and after a series of signal transduction, finally leading to intracellular calcium mobilization and protein kinase C activation. X-linked agammaglobulinemia (also called Bruton's syndrome, XLA) is a rare genetic disease. These XLA patients are unable to produce mature B cells. Normal B cells resist external infection by producing antibodies (called immunoglobulins). Due to the lack of B cells and antibodies, XLA patients are easy to obtain serious or even fatal infections. Further researches found that the direct reason that inhibits B-cell development is gene mutation of Btk. Thus it is proved that Btk plays an extremely important role in the development and function of normal B cells.
Btk becomes a remarkable drug target in cancers that are relevant to the B-cell, especially the B-cell lymphoma and leukemia.
Cells need BCR signals to grow and proliferate. Since Btk is an indispensable key member in the BCR signaling pathway, Btk inhibitors can block BCR signaling and induce apoptosis of cancer cells. Currently, there are two Btk inhibitors in the United States and Europe for clinical treatment of chronic lymphocytic leukemia (Cll) and small lymphocytic lymphoma (Sll): PCI-32765 (clinical phase III) and AVL-292 (clinical phase I). (See S E Herman et al. (2011), Blood 117 (23): 6287-96). Btk is also associated with acute lymphoblastic leukemia. Acute lymphoblastic leukemia is the most common cancer in children, and has a poor prognosis in adult patients. Genetic analysis found that the deficiency of BTK expression was found in all types of leukemia. Defective Btk protects leukemia cells from apoptosis.
Btk is also a therapeutic target for autoimmune diseases. Rheumatoid arthritis is a chronic autoimmune disease. Btk is an important component of BCR signaling in B cells and FC-γ signaling in bone marrow cells. Btk inhibitors are expected to reduce two main components of autoimmune diseases: pathogenic auto-antibodies produced by B cells and pro-inflammatory cytokine produced by myeloid cells. In cell experiments, it is proved that Btk inhibitors can effectively reduce auto-antibodies and pro-inflammatory cytokines. In mice with collagen-induced arthritis, Btk inhibitors reduced in vivo level of auto-antibodies and effectively controlled the disease. These results provide a new understanding of Btk functions during the development of B-cells or bone-marrow-cells driven diseases, and provide a convincing reason for targeting Btk in the treatment of rheumatoid arthritis. (See L A Honigberg et al. (2010), Proc Natl Acad Sci USA 107 (29): 13075-80. J A Di Paolo et al. (2011), Nat Chem Biol 7 (1): 41-50.)
The role of Btk in inflammatory diseases has been demonstrated by a rat basophilic leukemia cells (RBL-2H3) model. RBL-2H3 is a common model for mast cell inflammatory diseases research. Mast cells are rich of basophilic granules, and play a leading role in immunoglobulin E (IgE)-mediated allergic reactions. Small interfering RNA (siRNA), and LFM-A13 (an effective Btk inhibitor) can suppress the mast cell induced inflammatory response by inhibiting Btk activity. In the mast cells treated with siRNA and LFM-A13, the release of a pro-inflammatory mediator, histamine, is reduced by 20-25%.
It is also reported in literatures that Btk is used as a therapeutic target in heteroimmune diseases and thromboembolic diseases.
Therefore, the present disclosure aims to provide a novel compound for treating autoimmune diseases, heteroimmune diseases, inflammatory diseases, cancers, or thromboembolic diseases.